Review Article
Musculoskeletal Metastasis From Soft-tissue
Sarcomas: A Review of the Literature
Juan Pretell-Mazzini, MD
Crystal S. Seldon, MD
Gina D’Amato, MD
Ty K. Subhawong, MD
From the Musculoskeletal Oncology Division,
Department of Orthopedics, Miller School of
Medicine, University of Miami, Miami, FL (Pretell-
Mazzini), University of Miami/Jackson Memorial
Hospital Radiation Oncology Program, Miami, FL
(Seldon), Department of Medicine, Sarcoma
Medical Oncology, Sylvester Comprehensive
Cancer Center, University of Miami (D’Amato),
and the Department of Clinical Radiology and
Orthopedic Surgery (Subhawong), and the
Department of Radiology (Subhawong), Miller
School of Medicine, University of Miami.
None of the following authors or any immediate
family member has received anything of value
from or has stock or stock options held in a
commercial company or institution related
directly or indirectly to the subject of this article:
Pretell-Mazzini, Seldon, D’Amato, and
Subhawong.
J Am Acad Orthop Surg 2022;30:493-503
DOI: 10.5435/JAAOS-D-21-00944
Copyright 2022 by the American Academy of
Orthopaedic Surgeons.
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ABSTRACT
Soft-tissue sarcomas are a rare and extremely heterogeneous group of
cancers, representing ,1% of all human malignancies. The lungs are
the most common site of distant metastasis, followed by the bone,
lymph nodes, liver, brain, and subcutaneous tissue. Clinical
experience suggests that skeletal metastasis is part of the natural
history affecting the prognosis and quality of life in these patients.
Approximately 2.2% of patients have skeletal metastasis at diagnosis.
However, up to 10% will develop skeletal metastasis after a mean
interval of 21.3 months. Although systemic therapy with conventional
chemotherapy remains the primary treatment modality for those with
metastatic sarcoma, increased survival has been achieved in selected
patients who receive multimodality therapy, including surgery, for their
metastatic disease. The 5-year overall survival of patients with isolated
bone metastases was 41.2% (26.9% to 54.9%), which decreased to
32.9% (21.2% to 45.1%) in the setting of combined bone and lung
metastases. Moreover, the resection of the primary soft-tissue
sarcoma is a predictor of survival, resulting in a 58% decrease in
mortality after surgery (hazard ratio, 0.42, P = 0.013). Understanding
the effect of these metastases on patient survival may influence
imaging, surveillance, and treatment decisions.
S
oft-tissue sarcomas (STSs) are a rare, extremely heterogeneous group
of cancers, representing ,1% of human malignancies,1,2 with an
estimated 13,460 new cases in the United States in 2020.3
At initial diagnosis, most patients with STS have no detectable distant
disease2; however, almost 50% of patients can potentially develop metas-
tases to other organs, especially within 3 years of diagnosis.4 Generally, these
tumors have a propensity for hematogenous dissemination,5 and the lungs
are the most common site of distant metastasis, followed by the bone, lymph
nodes, liver, brain, and subcutaneous tissue.5
Musculoskeletal metastasis from STS and its clinical implications have
received little attention, although clinical experience suggests that they are a
late part of the natural history, representing a terminal stage of disease.1,5
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© American Academy of Orthopaedic Surgeons
Musculoskeletal Metastasis From STS
Understanding the tumor and patient characteristics
associated with these metastases and the effect on overall
survival and quality of life may influence imaging, sur-
veillance strategies, and treatment decisions. The aim of
this article was to comprehensively review the literature
to better understand this condition and be aware of
multidisciplinary approaches to care for these patients.
Epidemiology
Musculoskeletal metastasis from STS is uncommon. The
Scandinavian Sarcoma Group reported 1,195 surgical
skeletal metastases and found only 1.5% (18/1,195) of
cases were related to STS, with the proximal femur being
the most common location in long bones.6 The spine is
the most common skeletal metastatic site, as in carci-
nomas.5 These findings suggest that STS should be
considered in the differential of osseous metastasis, and
its implications for the final management and prognosis
of those patients should be examined.
Incidence
In a recent study using the Surveillance, Epidemiology,
and End Results registry, 8,234 patients were included,
and 180 (2.2%) patients presented with distant disease to
the bones at initial diagnosis.1 However, up to 10% of
STS patients may develop skeletal metastasis at some
point in their disease course.5 Yoshikawa et al5 reported
that skeletal metastasis appeared up to 66 months after
diagnosis, with a mean of 21.3 months.
Patient Characteristics
A slight predominance of men (52% to 62%)1,5 in their
mid-forties has been reported.5 Younis et al1 also
described a predominance of White (77.5%), insured
(71.9%), and single (44.9%) patients. Regarding the
primary tumor location, the lower limbs were the most
common sites in 55% to 75% of patients,1,5 followed by
the trunk in 19% to 23% of patients.5
Risk Factors
Several variables have been identified as risk factors for
developing skeletal metastasis such as high grade as
described by Younis et al,1 who found 3.6-fold increase
compared with lower grades (odds ratio [OR], 3.55,
P = 0.030). Regional lymph node involvement increased
the risk for developing isolated bone metastasis by 4.5
times (OR, 4.48, P = 0.008) and developing combined
lung and bone metastasis by 12.3 times (OR, 12.27,
P , 0.001).1 The histology of the STS is also very
important, as we will discuss later in this article.5
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Histology Type
Alveolar rhabdomyosarcoma (11.2%), followed by
spindle cell sarcoma (9%) and extraskeletal Ewing sar-
coma (7.8%), showed a higher incidence of isolated bone
metastasis at diagnosis, with leiomyosarcoma (16.48%)
presenting combined lung and bone metastasis.1
In other series including bone metastasis at any point,
alveolar soft part sarcomas (ASPS; 62.5%), dediffer-
entiated liposarcomas (50%), angiosarcomas (50%),
and rhabdomyosarcomas (31.3%) showed a higher bone
metastasis incidence.5
Of all types of STS, two are particularly interesting
because of their unique characteristics:
(1) Myxoid liposarcoma (MLS): It shows an
unusual pattern of metastasis including the ret-
roperitoneum, opposite extremity, and axilla,
even before metastasis to the lungs. Approxi-
mately one-third of cases will present metastasis,
and up to 17% of patients may develop skeletal
metastasis. Moreover, in 68% (27/40) of cases,
the first metastatic site is the bone.7 Finally, type
II (5-2) TLS-CHOP fusion transcripts present in
MLSs have been associated with an increased
incidence of bone metastasis.
(2) ASPS: Patients with this sarcoma can present a
high incidence of skeletal metastasis, even at
diagnosis. This high incidence may be partly due
to the long disease duration before the primary
tumor is diagnosed. This is an unusual tumor
because patients can have prolonged survival
with the late development of metastasis, with a
median time of 6 years; in addition, 38% of
metastases occur up to 10 years after diagnosis8
(Figure 1).
Pattern of Metastasis
As previously mentioned, the lungs are the most common
metastatic site from STS, due to hematogenous dissemi-
nation of disease. When present, bone metastases present
synchronously with lung metastases in approximately
87% (26/30) of cases, whereas 13% (4/30) of patients
may present with only bone metastasis.5 In approxi-
mately 57.1% (16/28) of cases, multiple lesions were
present5 (Figure 2). Most patients present with axial
metastasis, with the spine being the most common single
site.
MLSs present a higher incidence of muscle and sub-
cutaneous metastasis with subcutaneous locations in up
to 8.8% (14/159) and muscle locations in up to 6.2%
(10/159) of cases.7 Overall, muscle and subcutaneous
metastasis are less common than skeletal metastasis but
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Review Article
Figure 1

A, Coronal fat-suppressed T2-weighted MRI image demonstrating a hyperintense lateral left thigh mass with numerous serpentine
areas of hypointensity at the tumor periphery (arrows), a characteristic feature of ASPS, and representing flow voids from prominent
feeding vessels. B, Axial 18F-FDG PET-CT image taken 2 years after presentation showing an indeterminate soft-tissue nodule in the
left lateral chest wall, with only a low-level FDG-avidity. C, Ultrasonography image of this nodule demonstrating a hypoechoic mass
with minimal internal vascularity on Doppler interrogation, subsequently biopsied and proven to be metastatic ASPS. D, Axial 18F-FDG
PET-CT image taken 3.5 years after presentation revealing an FDG-avid bone metastasis to the proximal right femur. ASPS = alveolar
soft part sarcoma, FDG = fluorodeoxyglucose, PET = positron emission tomography.

can occur with any STS and often indicate advanced
disease and poor prognosis.
Clinical Approach
Most orthopedic surgeons will encounter patients with
metastatic bone disease at some point.9 Skeletal metastasis
may cause orthopedic problems, such as intractable pain
and pathologic fracture, which has been reported in up to
75% (21/28) of cases due to the osteolytic nature of these
lesions, and paresis when the spine is involved.5 Because
the spine is commonly affected, back pain is very common
and could be present in up to 68% (27/40) of patients.7
The development of impending or displaced patho-
logical fractures renders patients unable to ambulate or
perform activities of daily living without surgical stabi-
lization. The most common and upsetting concern of
these patients is a general decline in their quality of life.9
The general orthopedic surgeon should adopt a sys-
tematic approach for assessing musculoskeletal lesions
aimed at avoiding initial mistakes in management that
could adversely affect patient quality of life and poten-
tially affect prognosis.10
Impending Pathological Fractures
Metastatic bone disease leads to the deterioration of bone
metabolism with a subsequent loss of bone mechanical
function, putting the patient at risk for pathological
fracture. Most pathologic fractures occur in the peri-
trochanteric proximal femur, proximal humerus at the
surgical neck, and vertebral bodies.11

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Musculoskeletal Metastasis From STS
Figure 2
A, Sagittal fat-suppressed T2-weighted MRI shows a large lobulated myxoid liposarcoma in the posterior right thigh (arrows).
B, Contrast-enhanced CT of the chest demonstrates a skeletal metastasis to the sternum that has eroded through both the anterior and
posterior cortex, as well as a right lung metastasis (*). C, Axial contrast-enhanced fat-suppressed T1-weighted MRI demonstrates
numerous skeletal metastases in the pelvis (arrowheads).
The key factors needed to assess fracture risk are
patient symptomatology and the radiographic lesion
appearance.9
(1) Patient symptomatology: Mechanical pain at the
site of a known lower-limb metastasis very often
indicates an impending fracture.12
(2) Scoring systems for risk assessment:
• Harrington13 considered lesions that were
painful, larger than 2.5 cm, and involved more
than 50% of the cortex as the criteria for fracture
risk. Unfortunately, this system has not been val-
idated, and its use is debated.
• Mirels12 developed a scoring system based on the
presence or absence of pain and the size, location,
and radiographic appearance of the bone lesion,
and each of the 4 variables is assigned a score of 1
to 3 points. Although there is institutional and
surgeon variability in choice of thresholds for
surgical intervention, scores of 7 or lower can be
safely irradiated, whereas lesions scoring 9 or
higher require prophylactic fixation. Scores of 8
are in the gray zone and require clinical judge-
ment. Although this system has improved the
sensitivity of fracture prediction, the specificity
remains poor.14
• More advanced techniques for identifying high-
risk lesions for pathologic fracture using CT-based
finite element analysis are emerging15,16 but have
played limited roles in routine practice.
Compared with patients treated for a pathologic
fracture,17 those undergoing prophylactic intervention
have lower immediate postoperative mortality, longer
survival, shorter times to ambulation, and decreased
length of hospital stay.18 Therefore, educating all
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physicians who manage patients with cancer is essen-
tial to ensure that impending fractures are detected
early and treated adequately.
Overall Assessment of These Patients
When choosing the most appropriate treatment of pa-
tients with impending pathologic fractures, we should
consider the type of cancer, life expectancy, and general
health of the patient and the effect of any comorbidities.
Other relevant factors include tumor progression (sar-
comas are considered to have moderate growth, or
median survival time from 10 to 20 months, in prog-
nostic systems19), the number and types of previous
treatments, and the number of available treatments
that have not yet been used.10
Life expectancy and performance status (PS) are
factors of upmost importance to consider in the
decision-making process because they can affect the
eligibility of patients for adjuvant therapies:
(1) Life expectancy: The Tokuhashi score was ini-
tially developed for the surgical treatment of spine
metastasis and is also used to assess life expectancy
with long bone metastasis.19 Katagiri et al20
prospectively studied 808 patients with skeletal
metastasis who underwent nonsurgical (749 pa-
tients) versus surgical (59 patients) treatments and
identified six significant prognostic factors for
survival: the primary tumor (sarcomas are con-
sidered to have moderate growth or median sur-
vival time from 10 to 20 months), visceral or brain
metastasis, abnormal laboratory results, poor PS,
previous chemotherapy, and multiple skeletal
metastases. A prognostic score #3 was associated
with a 91% of 1-year survival rate and 78% of
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Review Article
Figure 3

A, Axial fat-suppressed T2-weighted MRI image of the elbow demonstrating a hyperintense mass (arrow) in the posterolateral soft
tissues, with marked peritumoral edema. B, Coronal image from surveillance 18F-FDG PET-CT approximately 1 year after presentation
showing soft-tissue metastases (arrows) in the right lateral chest well and right gluteus medius muscle. FDG = fluorodeoxyglucose, PET
= positron emission tomography.

2-year survival rate, while scores $7 carried a
27% of 6-month survival rate and only a 6% of 1-
year survival rate.
(2) PS: The PS describes the symptoms and functions
regarding ambulatory status and need for care. PS
0 indicates normal activity, PS 1 indicates some
symptoms but still nearly fully ambulatory, PS 2
indicates less than 50%, PS 3 indicates more than
50% of daytime in bed, and PS 4 indicates
completely bedridden. The Eastern Cooperative
Oncology Group criteria are widely used to assess
the PS system, and a recent study showed no
significant variations among the interpretations
of healthcare professionals.21
Radiological Assessment and Modalities
for Staging and Surveillance
Initial staging of STSs should assess the extent of both
local and distant disease. While contrast-enhanced MRI
is routinely performed for primary tumor characteriza-
tion, distant disease can be assessed by several modalities,
including radiographs, CT, positron emission tomogra-
phy (PET)-CT, and whole-body MRI (WB-MRI).
Modality choice is driven by histology-specific patterns
of spread, but institutional practice norms and resource
availability may also influence such decisions.
Because most STSs metastasize to the lungs, an initial
staging strategy that includes noncontrast chest CT is the
consensus recommendation by the American College
of Radiology. However, the American College of
Radiology guidelines do not advocate for a general
screening strategy for extrathoracic soft-tissue metas-
tases from STS or for distant osseous metastases
from STS in asymptomatic patients. When patients
have symptoms from possible skeletal metastases,
PET-CT is considered usually appropriate (Figure 3),
with bone scintigraphy or WB-MRI as secondary
options.22
Most STS extrathoracic metastases occur among rel-
atively few histologic subtypes. Steffner and Jang23
acknowledged that while abdominal and pelvic CT are
recommended by the National Comprehensive Cancer
Network for MLS, epithelioid sarcoma, leiomyosarco-
ma, and angiosarcoma, its routine use in other subtypes
has not been supported by data.
Fuglo et al24 found that at the initial staging of 59
STSs, PET-CT revealed 15 distant nonnodal metastases,
but these primarily involved only three STS subtypes:
liposarcoma, leiomyosarcoma, and epithelioid sarcoma.
Other authors have also advocated for selectively using
PET-CT at initial staging in only STS subtypes with a
higher risk for extrathoracic metastatic spread, such as
ASPS, leiomyosarcoma, MLS, and epithelioid sarcoma
subtypes.25 In a large series of 930 PET-CT scans per-
formed in high-grade sarcomas, Macpherson et al26
found that 134 (14%) resulted in clinical upstaging of
disease, primarily because of the detection of occult
metastases in the bone, muscle and viscera. Among STSs

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Musculoskeletal Metastasis From STS

Figure 4

A, AP radiograph of the right shoulder in a patient with a history of high-grade undifferentiated pleomorphic giant cell rich STS showing
a mixed lytic and sclerotic lesion in the proximal humerus with periosteal reaction laterally and medially in the metaphysis. B, Coronal
fat-suppressed T2-weighted MRI image demonstrating the proximal humerus metastases as an aggressive heterogeneously
hyperintense mass replacing normal marrow, with cortical breakthrough (arrow) and associated periosteal reaction. C, Postoperative
radiograph after radical resection of the proximal humerus showing the reconstructed shoulder with proximal humeral endoprosthesis
and total reverse shoulder arthroplasty. D, Coronal 18F-FDG PET-CT taken 2.5 years after resection showing no evidence of disease
recurrence. Note focal FDG avidity in the ipsilateral antecubital fossa related to injection site. FDG = fluorodeoxyglucose, PET =
positron emission tomography, STS = soft-tissue sarcoma.

in this study, PET-CT particularly influenced staging
for leiomyosarcoma, rhabdomyosarcoma, ASPS, and
malignant peripheral nerve sheath tumor.
In MLS, the frequency of extrapulmonary metastases,
comprising between 55% and 100% of metastases in
some series,27 demands special consideration when
devising staging strategies. Schwab et al28 reported that
in 230 patients with MLS, 40 (17%) developed skeletal
metastases, comprising 56% of all metastases. Bone
scintigraphy and PET-CT showed only a 16% and 14%
sensitivity, respectively, in a series of 33 patients with
spine metastases. Therefore, WB-MRI is emerging as a
consensus modality for MLS at initial staging and for
routine surveillance.
Treatment
The National Comprehensive Cancer Network guide-
lines recommend a multidisciplinary team approach to
care for these patients because treatment can be tailored
to specific sarcoma histology, patterns, and number of
metastases and the disease-free survival preceding
metastasis.29
The general patient condition should be optimized
with special interest in adjusting hypercalcemia when
present, liver and kidney function, coagulation pro-
files, and peripheral blood cell counts. This is of the
upmost importance in patients undergoing surgery
because a high 30-day postoperative complication rate
has been reported to be up to 31% of patients. These
patients are at high risk for infections and thrombo-
embolic events.19 Moreover, the risk of thrombo-
embolic events increases with disease stage.30 Factors
such as primary tumor growth (sarcoma is considered
intermediate), multiple bone metastasis, pathological
fracture, surgery of the lower extremities, low albu-
min levels, low sodium levels, and high white blood
cell counts have been associated with increased
morbidity.19
Surgery
In the initial management of patients with impending
or pathological fractures, achieving adequate pain
control with analgesics, local or regional blocks, and
splints/traction is advisable. In these cases, prophy-
lactic antibiotic therapy should be given for 24 hours
with a second-generation cephalosporin or vancomy-
cin.31 Special attention must be given to antith-
rombotic therapy because metastatic fractures are
associated with a high risk of thrombosis.
The goals of surgical treatment are to alleviate pain,
reduce narcotic use, restore skeletal stability, and regain
functional independence. To select the type of surgery,
several factors must be considered, including life expec-
tancy, comorbidities, disease extent, sarcoma type, and
anticipated future oncological treatments, considering
the relative resistance to radiation of these tumors.9
Surgical resection of metastasis is an appropriate
option if it renders a patient disease free.29 Solitary

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 Juan Pretell-Mazzini, MD, et al

Review Article
musculoskeletal metastasis can be treated with wide

EBRT = external beam radiation therapy, MSK = musculoskeletal, OS = overall survival, RT = radiation therapy, SBRT = stereotactic body radiation therapy, SRS = stereotactic surgery
as 1-5 lesions; 28.8% of

superior local control to

Oligometastatic defined

the cohort received RT

local excision to achieve disease-free intervals in fit

5 of 136 lesions were

hypofractionated RT
SBRT demonstrated
patients; however, whether survival is truly prolonged

(90.8% vs 84.1%)
remains controversial. This procedure is more accepted
Other

for better local control (LC) and preventing disease

progression, with the subsequent failure of fixation32

MSK
due to relative resistance to adjuvant therapy (Figure 4).
Multiple musculoskeletal metastases carry a poor
prognosis, and more conservative treatments can be
14 alive at
Median

45.3 mo

26.3 mo

16.9 mo
pursued. In general, the decision to use an endoprosthesis
OS

9 mo

or intramedullary device is based on bone stock being

sufficient to hold a stable construct, patient PS, and ex-
pected patient survival.33 Prosthetic reconstructions
progression in 9 mo
Clinical Studies Describing Radiation Therapy Options in Patients With Metastatic Soft-Tissue Sarcomas

Local Control

allow immediate postoperative stability and weight-

87.9% at 12 mo

bearing and are more durable than intramedullary nails,

15 without

with similar complication rates.32 However, in patients

with a short-term survival rate, an intramedullary nail
88%

with will provide sufficient stability.33

Equivalent to 50 Gy in 25

SRS: median dose 24 Gy

10-28 Gy in 1-5 fractions

Minimally Invasive Treatments for Local

median dose of 28.5 Gy
39 Gy in 13 fractions

Control
Hypofractionated:

Numerous minimally invasive approaches effectively

in 3-6 fractions
Dose

palliate pain from musculoskeletal metastases, including

thermal ablation (eg, radiofrequency ablation [RFA] and
fractions

cryoablation), osteoplasty, and embolization. Among

the advantages of these interventions is that biopsy to
confirm the diagnosis and treatment can often be per-
formed in a single visit, and repeat treatments are not
Treatment Modality

hypofractionated RT

constrained by radiation dose toxicity concerns. Most

guidelines for determining patient eligibility for the local
SBRT versus

management of bone metastases are based on pain level,

PS, life expectancy, spinal stability, metastatic epidural
SBRT
EBRT

EBRT

spinal cord compression, and the extent of visceral

metastases.34
RFA is the most common technique for thermal
grade sarcomas with 120
oligometastatic sarcoma

symptomatic metastatic

ablation and delivers electric current through percuta-

88 patients with high-
No. of Patients

metastatic sarcoma

neously placed probes to produce ionic agitation (ie,

metastatic lesions
281 patients with

17 patients with

46 patients with

frictional heating). RFA zones are limited in size to

approximately 3 to 4 cm and less effectively treat highly
sarcoma

sclerotic bone metastases due to tissue impedance.35

Cryoablation, another popular thermal ablation
strategy, relies on multiple cycles of freezing (down
to 240 °C) and thawing to destroy the tumor. The
Retrospective

Retrospective

Retrospective

Retrospective
Nature of

induced cell death putatively owes to cell membrane

Study

disruption, osmotic shifts in tissue, vascular injury and

ischemia, and cryoimmunologic effects. The ability to
visualize the destruction zone (iceball) and simulta-
neously activate multiple probes affords more precise
Falk et al37
Table 1.

Stragliotto

contouring of the ablation zone.36

et a139
Folkert
Soyfer
Study

et al38

et al40

The percutaneous injection of bone cement, such as

polymethylmethacrylate, can be used to provide added

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 Table 2
500

Musculoskeletal Metastasis From STS

Author and Year Study Design Treatment Regimen Efficacy Data Histology Approval
Copyright © the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.

Combination QT
Liu et al42 (2020) Retrospective Vincristine/Irinotecan/ ORR 50% Desmoplastic small round cell NCCN
study Temozolomide tumor
Setty et al43 (2018) Retrospective Vincristine/irinotecan/ CRR 0% (0/15), PRR 0 (0/15), Rhabdomysarcoma NCCN
study temozolomide SD 26.7% (4/15), PD 73.3%
(11/17), overall CBR 26.7%, 3-
mo PFS 23%
Wagner et al44 (2017) Retrospective Vincristine/doxorubicin/ 83% radiological response Ewing sarcoma NCCN
study ifosfamide
Single agent QT
JAAOS®

Demetri et al45 (2016) Phase 3 RCT Trabectedin mPFS 4.2 mo, 9.9 ORR, 51% Leiomyosarcoma and FDA
SD liposarcoma
Schöffski et al46 (2016) Phase 3 RCT Eribulin Median OS 13.5 mo, mPFS Leiomyosarcoma and FDA (liposarcoma) and
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2.6 mo, 4% ORR, 52% SD liposarcoma NCCN (leiomyosarcoma)
June 1, 2022, Vol 30, No 11

Molecular targeted therapy

Doebele et al47 (2020) Phase 1 and 2 Entrectinib 57% ORR NTRK fusion-positive solid FDA
RCT tumors
Heinrich et al48 (2020) Phase 1 RCT Avapritinib ORR 88%, CBR 98% GIST D842 kit mutation FDA
49
Gounder et al (2020) Phase 2 RCT Tazemetostat Median PFS 5.5 mo, 15% Epitheloid sarcoma FDA
ORR, 26% disease control
Immunotherapy
----- Tawbi et al50 (2017) Phase 2 RCT Pembrolizumab 40% ORR Undifferentiated pleomorphic NCCN
© American Academy of Orthopaedic Surgeons

sarcoma

AS = angiosarcoma, CBR = clinical benefit rate, CRR = complete response rate, DFS = disease-free survival, GIST = gastrointestinal stromal tumor, IMT = inflammatory myoblastic tumor,
mDFS = mean disease-free survival, mPFS = mean progression-free survival, MPNST = malignant peripheral nerve sheath tumor, NCCN = National Comprehensive Cancer Network, NTRK =
neurotrophic tyrosine receptor kinase, ORR = overall response rate, OS = overall survival, PD = progressive disease, PEComa = perivascular epitheliod cell tumor, PFR = progression-free
rate, PFS = progression-free survival, PRR = partial response rate, QT = chemotherapy, RCT = randomized controlled trial, SD = stable disease, TTP = time to progression

structural stability in compromised bone from metastatic
disease. Generally, those lytic lesions in anatomic regions
subjected to higher compressive loads are the most
favorable treatment candidates. The sites for which this
strategy most frequently succeeds are the vertebral bod-
ies, acetabulum, and the ends of long bones. In the spine
and pelvic ring, durable pain control is achieved in 60%
to 85% of patients.35
The goal of transarterial embolization is to eliminate
blood flow to targeted tumors; thus, hypervascular
bone and soft-tissue metastases are amenable to this
treatment. Transarterial embolization may be used
preoperatively to mitigate the risk of intraoperative
tumor hemorrhage or palliatively suppress spontaneous
bleeding from nonsurgical metastases. Permanent
embolic material is most frequently used for palliation
in metastatic disease, with up to a 50% reduction in pain
scores and analgesic requirements and an average of
9 months of pain relief.6
Radiation Therapy
Although the approach for managing musculoskeletal
metastatic lesions from STSs may include surgical resec-
tion, not all patients are eligible for surgery. Previously,
radiation therapy was reserved for the palliation of these
lesions; however, with advances in treatment modalities,
such as stereotactic body radiation therapy and intensity-
modulated radiation therapy, radiation therapy is
increasingly used for LC in this setting. These modalities
allow for high doses of radiation to be precisely delivered
to metastases while minimizing the dose to normal adja-
cent structures, thereby reducing treatment toxicity.
Only limited data available on radiation therapy in
sarcoma metastasis to musculoskeletal sites. Retrospec-
tive studies evaluated the feasibility and efficacy of
radiation therapy in metastatic settings37-40 (Table 1).
No data exist to support dose escalation in palliatives
setting for sarcoma patients, and general palliation doses
are used. Folkert et al40 demonstrated that in patients with
high-grade sarcoma with spinal metastasis, stereotactic
body radiation therapy provided better LC than hypo-
fractionated regimens (12-month LC of 90.8% [confi-
dence interval, 83% to 98.6%] vs 84.1 [confidence
interval, 72.9% to 95.3%], P = 0.007) (Table 1).
Systemic Therapy
The selection of systematic treatments for metastatic
STS is multifactorial. Understanding two main factors,
the disease and the patient, will help determine treat-
ment goals, which will in turn help select the optimal
therapy. Important disease factors include the extent of
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JAAOS® June 1, 2022, Vol 30, No 11 © American Academy of Orthopaedic Surgeons
Copyright © the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
Juan Pretell-Mazzini, MD, et al
Review Article
metastatic disease, organ involvement, whether addi-
tional tumor growth will lead to severe motor dys-
function, and how disease aggressiveness. Evaluating
disease aggressiveness can include but is not limited to
the histologic subtype, the timing of metastasis (ranging
from several years after a cure or at disease presenta-
tion), and previous treatments.41 Important patient
factors included age, PS, comorbidities, pain level,
motor function, previous treatment, and willingness to
undergo treatment.10,17,20
As previously stated, systemic treatment options
strongly depend on histologic subtype. In general, com-
bination chemotherapy provides the highest chance of
response in exchange for the highest toxicity rates.42-44
Single-agent chemotherapy, while less toxic, is less likely
to generate a response.45,46 Most targeted agents result
in disease stabilization unless they target a specific
receptor activated by a specific mutation, such as the
KIT receptor in gastrointestinal stromal tumor, the
anaplastic lymphoma kinase fusion protein in inflam-
matory myofibroblastic tumor, and the neurotrophic
tyrosine receptor kinase fusion protein in 1% of sar-
comas harboring that mutation. These highly specific
targeted therapies can have extremely high response
rates.47-49 The use of immunotherapy is limited to
specific subtypes and clinical trials4,50 (Table 2).
Summary
STSs are a rare, extremely heterogeneous group of can-
cers, representing ,1% of human malignancies. The
lungs are the most common site of distant metastasis.
Clinical experience suggests that skeletal metastasis is
part of the natural history affecting the prognosis and
quality of life of patients. Approximately 2.2% of cases
were reported at diagnosis; however, up to 10% will
develop skeletal metastases. Several STS subtypes can
develop musculoskeletal metastasis at diagnosis or
during the disease course, and considering them is
important so that the appropriate staging and treatment
can be administered. Although systemic therapy with
conventional chemotherapy remains the primary treat-
ment modality for those with metastatic sarcoma,
increased survival has been achieved in selected patients
who received multimodality therapy, including surgery.
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501
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JAAOS® June 1, 2022, Vol 30, No 11 © American Academy of Orthopaedic Surgeons
Copyright © the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
Juan Pretell-Mazzini, MD, et al
Review Article
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